Major histocompatibility complex encoded class I molecules are integrally involved in the presentation of viral antigens to cytotoxic T lymphocytes (CTL). The goal of these studies is to gain an understanding of the regulation of expression, and the functional and antigenic properties of these molecules. Research has focused on the fact that multiple class I molecules can be generated from single genes by alternative splicing of pre- mRNAs. The alternative class I forms vary in expression in different cell types and in their ability to undergo phosphorylation. It is tempting to speculate that alternative splicing may influence function by controlling the phosphorylation of class I molecules. The complexity of the murine H-2D region was further underlined by the discovery of additional D-region encoded molecules in the H-2 alpha haplotype and the delineation of a new family of D-region molecules which suggests a strong role for unequal crossing over in the evolution of D-region genes. Multiple species were examined for the expression of soluble class I molecules equivalent to the murine Q10 molecule. Only members of the order Perrissodactyla were found to have such a molecule suggesting that independent evolutionary events created class I genes of similar function. In the human, the cloning and sequence analysis of the HLA-A11 gene revealed that the close antigenic relationship of HLA-A3 and HLA-A11 was founded in their high structural homology and was likely related to a shared glutamine residue at position 62. From this data, a predicted cross-reactive recognition by CTL between the rare HLA-A3 subtype, HLA-A11 was confirmed and offered support for the critical role of amino acid positions 152 and 156 in CTL recognition of class I molecules.